This year, we continued to study the role of mismatch repair in regulating the genome-wide mutation rates of yeast cells harboring variant, proofreading-deficient alleles of the major leading and lagging strand enzymes, DNA polymerases epsilon and delta. These studies, which are being performed in mismatch repair proficient and deficient yeast cells, as reported in the other annual report from this laboratory, 1 Z01 ES065070-27: Structure-Function Studies of DNA Replication Fidelity. In addition, this year we published the development of a new technology that greatly improves our ability to measure genome-wide mutation rates in MMR-deficient and proficient cells. This technology is very informative regarding the contributions of nucleotide selectivity, proofreading and mismatch repair to genome wide mutation rates for base substitution and insertion-deletion errors. It will be used in most future studies.